Solid forms of [(1 s)-1 -[(2s,4r,5r)-5-(5-amino-2-oxo-thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxy-tetrahydrofuran-2-yl]propyl] acetate

ABSTRACT

The present invention relates to novel solid forms of compound (I) [(1S)-1-[(2S,4R,5R)-5-(5-amino-2-oxo-thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxy-tetrahydrofuran-2-yl]propyl] acetate and pharmaceutical compositions comprising the solid forms thereof disclosed herein, which may be used as a TLR7 agonist, or for the treatment or prophylaxis of a viral disease in a patient relating to HBV infection or a disease caused by HBV infection.

The present invention relates to novel solid forms of compound (I),

[(1S)-1-R2S,4R,5R)-5-(5-amino-2-oxo-thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxy-tetrahydrofuran-2-yl]propyl]acetate and pharmaceutical compositions comprising solid forms thereofdisclosed herein, which may be used as a TLR7 agonist, or for thetreatment or prophylaxis of a viral disease in a patient relating to HBVinfection or a disease caused by HBV infection.

BACKGROUND OF THE INVENTION

The current therapy of chronic HBV infection is based on two differenttypes of drugs: the traditional antiviral nucleoside/nucleotideanalogues and the more recent Pegylated IFN-α (PEG-IFN-α). The oralnucleoside/nucleotide analogues act by suppressing the HBV replication.This is a life-long course of treatment during which drug resistanceoften occurs. As an alternative option, Pegylated IFN-α (PEG-IFN-α) hasbeen used to treat some chronic infected HBV patients within finitetherapy duration. Although it has achieved seroconversion in HBeAg atleast in a small percentage of HBV patients, the adverse effect makes itpoorly tolerable. Notably, functional cure defined as HBsAgseroconversion is very rare with both current therapies. A newgeneration therapeutic option to treat HBV patients for a functionalcure is therefore of urgent need. Treatment with an oral TLR7 agonistrepresents a promising solution to provide greater efficacy with bettertolerability. Pegylated IFN-α (PEG-IFN-α) is currently used to treatchronic HBV and is an alternative to potentially life-long treatmentwith antiviral nucleoside/nucleotide analogues. In a subset of chronicHBV patients, PEG-IFN-α therapy can induce sustained immunologic controlof the virus following a finite duration of therapy. However, thepercentage of HBV patients that achieve seroconversion with interferontherapy is low (up to 27% for HBeAg-positive patients) and the treatmentis typically poorly tolerated. Furthermore, functional cure (defined asHBsAg loss and seroconversion) is also very infrequent with bothPEG-IFN-α and nucleoside/nucleotide treatment. Given these limitations,there is an urgent need for improved therapeutic options to treat andinduce a functional cure for chronic HBV. Treatment with an oral,small-molecule TLR7 agonist is a promising approach that has thepotential to provide greater efficacy and tolerability.

[(1S)-1-[(2S,4R,5R)-5-(5-amino-2-oxo-thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxy-tetrahydrofuran-2-yl]propyl]acetate (compound (I)) was disclosed in WO2016091698 as an effectiveTLR7 agonist.

It was found that Form Amorphous of compound (I) was prone tocrystallization which leads to form change and makes it not suitable forfurther drug development. As one of the objectives of this patent,several novel solid forms were identified and characterized, showingsignificantly improved stability compared with Form Amorphous ofcompound (I). Meanwhile, developing novel crystalline forms of compound(I) with good processability or acceptable aqueous solubility is alsoone of the objectives of current invention. Some novel solid formsenhanced the developability of compound (I) fundamentally.

The present disclosure relates generally to the novel solid forms ofcompound (I) and processes to make them.

In another embodiment, Form C of compound (I) shows significantlyimproved stability and comparable apparent solubility compared with FormAmorphous of compound (I) and/or other solid forms. The physicalstability of drug substances is an integral part of the systematicapproach to the stability evaluation of pharmaceuticals due to itspotential impacts on drug chemical stability performance and safety. Thegreater the stability is, the longer the shelf life could be. Thereforethe accelerated and long term stability testing used in this inventioncould be used to predict shelf lives. Furthermore, solubility is one ofthe important parameters to achieve desired concentration of drug insystemic circulation for desired pharmacological response. Generallyspeaking, amorphous pharmaceuticals are markedly more soluble than theircrystalline counterparts. Surprisingly, Form C of compound (I) showscomparable apparent solubility compared with Form Amorphous of compound(I) and ensures the in vivo absorption. The unexpected propertyimprovement of Form C makes it more suitable for further drugdevelopment.

In another embodiment, Form D of compound (I) is an ethyl acetatesolvate.

In another embodiment, Form E of compound (I) is a process related formwhich exhibits excellent impurity purification effect.

The bioavailability of many drugs can be dependent on polymorphs thatshow different solubility and absorption rate. Moreover, in vivoconversion of the prodrug to active form was confirmed to bepolymorph-dependent. Compound (I) is a double prodrug, the conversionfrom double prodrug to single prodrug and active form can be dependenton the solid forms of this invention. The SDPK study was performed onForm A and C to demonstrate such effect. As the result, Form A ofcompound (I) exhibits faster conversion rate (shorter T_(max) and higherC_(max)) to the single prodrug and high C_(max) of active form in vivostudy, and therefore Form A of compound (I) is more preferred withimmediate-release oral formulation.

In another embodiment, Form B of compound (I) is more preferred withoral suspension formulation. Conversion of Form Amorphous of compound(I) or Form A of compound (I) to Form B of compound (I) in aqueouscompositions was observed. Therefore, Form B of compound (I) showsbetter stability in aqueous environment.

In another embodiment, Form G of compound (I) shows improved stabilityand comparable apparent solubility compared with Form Amorphous ofcompound (I). With regard to general solid formulation development, themelting point of a synthetic substance should not be below 80° C.(Stefan Balbach, 2004, Pharmaceutical evaluation of early developmentcandidates “the 100 mg-approach”, International Journal of Pharmaceutics275 (2004) 1-12). Form C, F and G of compound (I) with the onset meltingpoint at 128.9° C., 141.2° C. and 122.0° C. respectively are thereforemuch more preferred with respect to solid formulation developmentcompared to the other forms of this invention.

SUMMARY OF THE INVENTION

The present invention relates to polymorphs, salts, solvates,co-crystals or combinations thereof and methods for the synthesis andproduction of solid forms of[(1S)-1-[(2S,4R,5R)-5-(5-amino-2-oxo-thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxy-tetrahydrofuran-2-yl]propyl]acetate.

In one embodiment, provided herein is an amorphous or solid form ofcompound (I) or solvates or combination thereof.

In another embodiment, provided herein is an amorphous or solid form ofcompound (I), wherein the solid form is Form A, Form B, Form C, Form D,Form E, Form F, Form G, Form H, Form I or Form J, or a combinationthereof.

In another embodiment, the solid form of compound (I) is Form C thatexhibits an X-ray powder diffraction (XRPD) pattern with characteristicpeaks expressed in degrees 2-theta at 6.0°±0.2°, 11.3°±0.2°, 15.4°±0.2°,16.2°±0.2°, 20.0°±0.2°, 21.4°±0.2°, 24.6°±0.2° and 26.1°±0.2°.

In a further embodiment, the solid form of compound (I) is Form C thatexhibits an X-ray powder diffraction (XRPD) pattern with characteristicpeaks expressed in degrees 2-theta at 6.0°±0.2°, 11.3°±0.2°, 13.2°±0.2°,15.4°±0.2°, 16.2°±0.2°, 18.1°±0.2°, 19.3°±0.2°, 20.0°±0.2°, 21.4°±0.2°,23.5°±0.2°, 24.6°±0.2°, 25.6°±0.2°, 26.1°±0.2° and 32.5°±0.2°.

In a further embodiment, the solid form of compound (I) is Form C thatexhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 3

In a further embodiment, the solid form of compound (I) is Form C with adifferential scanning calorimetry (DSC) thermogram comprisingendothermic peak with onset temperature at 128.9° C.±3° C.

In another embodiment, the solid form of compound (I) is Form D thatexhibits an X-ray powder diffraction (XRPD) pattern with characteristicpeaks expressed in degrees 2-theta at 6.6°±0.2°, 17.5°±0.2°, 20.5°±0.2°,20.8°±0.2°, 26.1°±0.2° and 28.7°±0.2°.

In a further embodiment, the solid form of compound (I) is Form D thatexhibits an X-ray powder diffraction (XRPD) pattern with characteristicpeaks expressed in degrees 2-theta at 6.6°±0.2°, 10.9°±0.2°, 11.2°±0.2°,15.3°±0.2°, 17.1°±0.2°, 17.5°±0.2°, 19.0°±0.2°, 20.5°±0.2°, 20.8°±0.2°,22.1°±0.2°, 24.2°±0.2°, 25.4°±0.2°, 26.1°±0.2°, 28.7°±0.2° and33.3°±0.2°.

In a further embodiment, the solid form of compound (I) is Form D thatexhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 6.

In a further embodiment, the solid Form D is an ethyl acetate solvate ofcompound (I).

In a further embodiment, the solid form is Form D with the X-ray crystalstructure showed in FIG. 7.

In a further embodiment, Form D is an ethyl acetate solvate of compound(I).

In another embodiment, the solid form of compound (I) is Form E thatexhibits an X-ray powder diffraction (XRPD) pattern with characteristicpeaks expressed in degrees 2-theta at 6.4°±0.2°, 7.4°±0.2°, 7.6°±0.2°,9.0°±0.2°, 13.4°±0.2°, 16.2°±0.2° and 21.7°±0.2°.

In a further embodiment, the solid form of compound (I) is Form E thatexhibits an X-ray powder diffraction (XRPD) pattern with characteristicpeaks expressed in degrees 2-theta at 6.4°±0.2°, 7.4°±0.2°, 7.6°±0.2°,9.0°±0.2°, 9.7°±0.2°, 13.4°±0.2°, 14.4°±0.2°, 15.7°±0.2°, 16.2°±0.2°,18.2°±0.2°, 21.0°±0.2°, 21.3°±0.2°, 21.7°±0.2°, 23.5°±0.2° and25.5°±0.2°.

In a further embodiment, the solid form of compound (I) is Form E thatexhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 2.

In another embodiment, the solid form of compound (I) is Form A thatexhibits an X-ray powder diffraction (XRPD) pattern with characteristicpeaks expressed in degrees 2-theta at 3.7°±0.2°, 6.5°±0.2°, 7.5°±0.2°,12.6°±0.2°, 15.2°±0.2°, 16.4°±0.2°, 22.4°±0.2°, 22.7°±0.2° and23.4°±0.2°.

In a further embodiment, the solid form of compound (I) is Form A thatexhibits an X-ray powder diffraction (XRPD) pattern with characteristicpeaks expressed in degrees 2-theta at 3.7°±0.2°, 6.5°±0.2°, 7.5°±0.2°,12.1°±0.2°, 12.6°±0.2°, 15.2°±0.2°, 16.4°±0.2°, 16.9°±0.2°, 20.8°±0.2°,21.4°±0.2°, 22.1°±0.2°, 22.4°±0.2°, 22.7°±0.2°, 23.4°±0.2°, 24.6°±0.2°,26.2°±0.2°, 26.2°±0.2° and 26.8°±0.2°.

In a further embodiment, the solid form of compound (I) is Form A thatexhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 8.

In another embodiment, the solid form of compound (I) is Form B thatexhibits an X-ray powder diffraction (XRPD) pattern with characteristicpeaks expressed in degrees 2-theta at 4.9°±0.2°, 6.5°±0.2°, 8.3°±0.2°,13.3°±0.2°, 13.6°±0.2°, 24.5°±0.2° and 25.9°±0.2°.

In a further embodiment, the solid form of compound (I) is Form B thatexhibits an X-ray powder diffraction (XRPD) pattern with characteristicpeaks expressed in degrees 2-theta at 4.9°±0.2°, 6.5°±0.2°, 8.3°±0.2°,10.0°±0.2°, 10.3°±0.2°, 13.3°±0.2°, 13.6°±0.2°, 14.7°±0.2°, 18.3°±0.2°,19.3°±0.2°, 20.6°±0.2°, 22.3°±0.2°, 23.1°±0.2°, 24.5°±0.2°, 25.3°±0.2°and 25.9°±0.2°.

In a further embodiment, the solid form of compound (I) is Form B thatexhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 9.

In another embodiment, the solid form of compound (I) is Form G thatexhibits an X-ray powder diffraction (XRPD) pattern with characteristicpeaks expressed in degrees 2-theta at 5.9°±0.2°, 12.6°±0.2°, 15.9°±0.2°,21.6°±0.2°, 24.5°±0.2° and 24.7°±0.2°.

In a further embodiment, the solid form of compound (I) is Form G thatexhibits an X-ray powder diffraction (XRPD) pattern with characteristicpeaks expressed in degrees 2-theta at 5.9°±0.2°, 9.6°±0.2°, 12.6°±0.2°,15.9°±0.2°, 17.9°±0.2°, 19.9°±0.2°, 21.6°±0.2°, 24.5°±0.2°, 24.7°±0.2°,26.3°±0.2°, 29.1°±0.2°, 32.7°±0.2° and 33.1°±0.2°.

In a further embodiment, the solid form of compound (I) is Form G thatexhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 10.

In a further embodiment, the solid form of compound (I) is Form G with adifferential scanning calorimetry (DSC) thermogram comprisingendothermic peak with onset temperature at 122.0° C.±3° C.

In another embodiment, the solid form of compound (I) is Form F thatexhibits an X-ray powder diffraction (XRPD) pattern with characteristicpeaks expressed in degrees 2-theta at 7.4°±0.2°, 11.2°±0.2°, 16.0°±0.2°,16.4°±0.2°, 17.2°±0.2°, 21.0°±0.2°, 25.0°±0.2° and 25.5°±0.2°.

In a further embodiment, the solid form of compound (I) is Form F thatexhibits an X-ray powder diffraction (XRPD) pattern with characteristicpeaks expressed in degrees 2-theta at 7.4°±0.2°, 9.8°±0.2°, 11.2°±0.2°,15.7°±0.2°, 16.0°±0.2°, 16.4°±0.2°, 17.2°±0.2°, 18.1°±0.2°, 18.8°±0.2°,19.2°±0.2°, 21.0°±0.2°, 21.2°±0.2°, 22.9°±0.2°, 25.0°±0.2°, 25.5°±0.2°,25.7°±0.2° and 29.1°±0.2°.

In a further embodiment, the solid form of compound (I) is Form F thatexhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 16.

In a further embodiment, the solid form of compound (I) is Form F with adifferential scanning calorimetry (DSC) thermogram comprisingendothermic peak with onset melting temperature at 141.2° C.±3° C.

In another embodiment, the solid form of compound (I) is Form H thatexhibits an X-ray powder diffraction (XRPD) pattern with characteristicpeaks expressed in degrees 2-theta at 11.4°±0.2°, 15.6°±0.2°,17.3°±0.2°, 21.1°±0.2° and 21.9°±0.2°.

In a further embodiment, the solid form of compound (I) is Form H thatexhibits an X-ray powder diffraction (XRPD) pattern with characteristicpeaks expressed in degrees 2-theta at 6.7°±0.2°, 9.4°±0.2°, 11.1°±0.2°,11.4°±0.2°, 15.6°±0.2°, 17.3°±0.2°, 17.6°±0.2°, 18.9°±0.2°, 19.5°±0.2°,21.1°±0.2°, 21.9°±0.2°, 23.2°±0.2°, 25.8°±0.2° and 29.0°±0.2°.

In a further embodiment, the solid form of compound (I) is Form H thatexhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 17.

In a further embodiment, Form H is a dimethyl carbonate solvate ofcompound (I).

In another embodiment, the solid form of compound (I) is Form I thatexhibits an X-ray powder diffraction (XRPD) pattern with characteristicpeaks expressed in degrees 2-theta at 11.1°±0.2°, 15.4°±0.2°,17.2°±0.2°, 17.6°±0.2°, 20.9°±0.2° and 21.7°±0.2°.

In a further embodiment, the solid form of compound (I) is Form I thatexhibits an X-ray powder diffraction (XRPD) pattern with characteristicpeaks expressed in degrees 2-theta at 9.4°±0.2°, 11.1°±0.2°, 13.8°±0.2°,14.2°±0.2°, 15.4°±0.2°, 17.2°±0.2°, 17.6°±0.2°, 19.2°±0.2°, 20.9°±0.2°,21.7°±0.2°, 22.0°±0.2°, 23.0°±0.2°, 24.0°±0.2°, 25.2°±0.2° and28.9°±0.2°.

In a further embodiment, the solid form of compound (I) is Form I thatexhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 18.

In a further embodiment, Form I is a methyl ethyl ketone solvate ofcompound (I).

In another embodiment, the solid form of compound (I) is Form J thatexhibits an X-ray powder diffraction (XRPD) pattern with characteristicpeaks expressed in degrees 2-theta at 8.9°±0.2°, 11.0°±0.2°, 16.4°±0.2°,19.8°±0.2°, 20.7°±0.2°, 23.7°±0.2° and 27.1°±0.2°.

In a further embodiment, the solid form of compound (I) is Form J thatexhibits an X-ray powder diffraction (XRPD) pattern with characteristicpeaks expressed in degrees 2-theta at 8.9°±0.2°, 11.0°±0.2°, 13.3°±0.2°,15.0°±0.2°, 16.4°±0.2°, 16.9°±0.2°, 19.8°±0.2°, 20.7°±0.2°, 22.6°±0.2°,23.7°±0.2°, 27.1°±0.2° and 33.4°±0.2°.

In a further embodiment, the solid form of compound (I) is Form J thatexhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 19.

In a further embodiment, Form J is a methyl isobutyl ketone solvate ofcompound (I).

In another embodiment, provided herein is a pharmaceutical compositioncomprising the solid form disclosed herein; and a pharmaceuticallyacceptable carrier, excipient, diluent, adjuvant, vehicle or acombination thereof.

In another embodiment, provided herein is the use of the solid formdisclosed herein or the pharmaceutical composition for the manufactureof a medicament for the treatment or prophylaxis of a viral disease in apatient.

In another embodiment, the viral disease disclosed herein is HBVinfection or a disease caused by HBV infection.

In another embodiment, provided herein is a method for the treatment orprophylaxis of HBV infection or a disease caused by HBV infection, whichmethod comprises administering a therapeutically effective amount of thesolid form or the pharmaceutical composition disclosed herein.

Abbreviations

C_(max) Maximum concentration observed

FaSSIF Fasted State Simulated Intestinal Fluid

FeSSIF Fed State Simulated Intestinal Fluid

DSC Differential scanning calorimetry

Pos. Position

Rel. Int. Relative Intensity

SGF Simulated Gastric Fluid

TGA Thermal gravimetric analysis

T_(max) Time at which the maximum concentration (Cmax) is observed

XRPD X-ray powder diffraction

DESCRIPTION OF THE FIGURES

FIG. 1 X-ray powder diffraction pattern for Form Amorphous

FIG. 2 X-ray powder diffraction pattern for Form E

FIG. 3 X-ray powder diffraction pattern for Form C

FIG. 4 DSC thermogram of Form C

FIG. 5 TGA diagram of Form C

FIG. 6 X-ray powder diffraction pattern for Form D

FIG. 7 X-ray crystal structure of Form D

FIG. 8 X-ray powder diffraction pattern for Form A

FIG. 9 X-ray powder diffraction pattern for Form B

FIG. 10 X-ray powder diffraction pattern for Form G

FIG. 11 DSC thermogram of Form E

FIG. 12 DSC thermogram of Form A

FIG. 13 DSC thermogram of Form B

FIG. 14 DSC thermogram of Form G

FIG. 15 DSC thermogram of Form F

FIG. 16 X-ray powder diffraction pattern for Form F

FIG. 17 X-ray powder diffraction pattern for Form H

FIG. 18 X-ray powder diffraction pattern for Form I

FIG. 19 X-ray powder diffraction pattern for Form J

EXAMPLES

The invention will be more fully understood by reference to thefollowing examples. They should not, however, be construed as limitingthe scope of the invention.

HPLC Method for Chemical Purity and Assay Test

HPLC condition is disclosed here in Table 1.

TABLE 1 HPLC conditions for chemical purity and assay test InstrumentAgilent 1260 with a DAD or VWD detector Column Waters Xbridge C8 (4.6 mm× 150 mm, 3.5 μm) or equivalent Column Temperature 30° C. Flow Rate 0.8mL/min Nominal 0.1 mg/mL Concentration Injection Volume 8 μL MobilePhase A 0.1% TFA in water Mobile Phase B 0.1% TFA in acetonitrileGradient Program Time (min) % A % B 0.00 98 2 3.00 98 2 15.00 10 9020.00 10 90 20.01 98 2 25.00 98 2 Diluent 50:50 water:acetonitrile (v/v)Detection UV 230 nm Retention Time 10.6 min

Example 1 Preparation of Form Amorphous of Compound (I).

A solution of 1.0 g of compound (I) in 7 mL of acetone was rapidlyevaporated using a rotary evaporator. The solid was dried under vacuumat 50° C. overnight. The solid was analyzed by XRPD. The result is shownin FIG. 1.

Characterization Method:

XRPD: X-ray diffraction patterns were recorded at ambient conditions intransmission geometry with a STOE STADI P powder diffractometer (STOE &Cie GmbH) with Cu-Kα1 radiation. The diffractometer was equipped with aprimary Ge beam monochromator and a silicon strip detector. Tube voltagewas 40 kV and tube current was 40 mA. Scan range was from 3 to 42 degree2-theta. The step size was 0.02 degree 2-theta with a measurement timeof 20 s per step.

Example 2

Preparation of Form E of compound (I)

Preparation of[(1S)-1-[(2S,4R,5R)-5-(5-amino-2-oxo-thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxy-tetrahydrofuran-2-yl]propyl]acetate citric acid (Compound (II))

The solution of[(1S)-1-R2S,4R,5R)-5-(5-amino-2-oxo-thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxy-tetrahydrofuran-2-yl]propyl]acetate (compound (I), 22.2 mol) in acetonitrile (69.5 kg) was heated to45° C.-52° C. and stirred at 45° C.-52° C. for 30 minutes. To themixture citric acid monohydrate (4.67 kg, 22.2 mol) and water (0.440 kg,V_(water)/V_(acetonitrile)=0.005) were charged. The resulting mixturewas stirred at 45° C.-52° C. for 4 hours then cooled to 0° C. over 10hours. The solid was separated via centrifuge and the wet cake waswashed with acetonitrile (1.0 kg), and dried in a vacuum oven (30 mmHg,40° C.) for 32 hours to afford compound (II) (9.04 kg, 74.5% yield). Theratio of compound (I) and citric acid in compound (II) was 1:1 based onNMR data.

Compound (II): ¹H NMR (400 MHz, d₆-DMSO) ppm: 8.34 (s, 1H), 6.91 (br.s., 2H), 5.82 (s, 1H), 5.46-5.58 (m, 1H), 4.70-4.82 (m, 2H), 4.14-4.23(m, 1H), 2.60-2.80 (m, 4H), 2.42-2.48 (m, 1H), 1.98 (s, 3H), 1.78-1.88(m, 1H), 1.55-1.70 (m, 1H), 1.34-1.49 (m, 1H), 0.82 (t, J=7.40 Hz, 3H).MS obsd. (ESI⁺) [(M+H)⁺]: 355.

Preparation of Form E of Compound (I)

A 50 L glass jacket reactor was charged with Na₂CO₃ (0.819 kg, 7.73 mol)and water (19.8 kg). The mixture was stirred at 20° C. to 30° C. for 30minutes and then isopropyl acetate (18.2 kg) and[(1S)-1-R2S,4R,5R)-5-(5-amino-2-oxo-thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxy-tetrahydrofuran-2-yl]propyl]acetate citric acid (compound (II)) (3.0 kg, 5.49 mol) were added. Thereaction mixture was stirred for another 3 hours at 20° C. to 30° C.After phase separation, the organic phase was washed with sat. Na₂CO₃aq. solution (20.2 kg), water (20.0 kg), sat. NaCl aq. solution (21.7kg). Such extraction was repeated twice. The combined organic solutionwas concentrated under vacuum to remove the volatile to afford a crudesolution (13.04 kg), to which isopropyl acetate (6.05 kg) was thenadded. The reaction mixture was then heated to 40° C. to 50° C. andstirred for 1 hour, followed by slow addition of n-heptane (8.05 kg).The resulting mixture was stirred at 40° C. to 50° C. for another 12hours. After slow cooling to 0° C. to 10° C. over 4 hours and stirred at0° C. to 10° C. for 30 minutes, n-heptane (10.1 kg) was added and theresulting mixture was maintained at 0° C. to 10° C. for 2 hours. Thesuspension was separated by vacuum filtration and the wet cake waswashed with n-heptane (6 kg) and dried in a vacuum oven (30 mmHg, 45°C.) for 19 hours.

The XRPD pattern of Form E of compound (I) is shown in FIG. 2. Majorpeaks and their related intensities in the XRPD pattern are shown inTable 2. Depending on the solvation status Form E can be a solvate (isostructural with different solvents) or a polymorph of compound (I).

Characterization Method:

DSC analysis: TA Q2000, 30-200° C., heating rate 10° C./min.

XRPD: PANalytical EMPYREAN X-ray powder diffractometer with Cu-Kαradiation. Tube voltage was 40 kV and tube current was 40 mA. Scan rangewas from 4 to 40 degree 2-theta. The step size was 0.026° at a scanningspeed of 3.463°/min.

TABLE 2 X-Ray Powder Diffraction peaks of Form E of compound (I). Pos.[°2-theta] Rel. Int. [%] 6.4 41 7.4 56 7.6 100 8.2 15 8.7 16 9.0 41 9.737 10.6 17 11.2 19 11.7 6 12.2 19 12.7 10 13.4 53 13.8 16 14.4 31 14.711 15.0 8 15.4 15 15.7 37 16.2 42 16.4 23 16.7 8 17.4 11 17.9 11 18.2 3718.4 22 18.7 6 18.9 6 19.2 8 19.6 13 20.1 10 20.3 30 20.6 6 21.0 38 21.338 21.7 46 22.3 23 22.6 27 22.8 11 23.5 34 24.2 13 24.5 20 24.8 20 25.534 25.7 23 26.1 17 26.5 28 27.1 15 27.8 14 28.0 15

DSC result shown in FIG. 11 indicates Form E of compound (I) has anonset of endothermal event at around 76.4° C.

Example 3 Alternative Preparation of Form E of Compound (I)

Approximate 50 mg of Form Amorphous of compound (I) as prepared inExample 1 was weighed and transferred to a glass vial. 0.1 mL ofisopropyl acetate was added to form a clear solution. 0.4 mL ofn-heptane was added to the solution. The vial was mounted to a shakerand kept shaking at 25° C. with 1200 rpm for 4 h to generateprecipitation. The solid precipitate was collected for XRPD analysis.The XRPD pattern of solid was same as that in Table 2 and confirmed tobe Form E of compound (I).

Example 4 Preparation of Form C of Compound (I).

A 50 L glass jacket reactor was charged with water (35.65 kg), EtOH(3.00 kg) and 3.15 kg of Form E of compound (I) as prepared in Example2. The mixture was heated to 40° C. to 50° C. and stirred for 19 hours.Then, after cooling to 0° C. to 10° C. over 4 hours, a suspension formedand was separated via vacuum filtration. The wet cake was washed withwater (5.00 kg) twice and then dried in a vacuum oven (30 mmHg, 50° C.)for 24 hours. The solid was collected for XRPD analysis, DSC analysis,and TGA analysis.

The XRPD pattern of Form C of compound (I) is shown in FIG. 3. Majorpeaks and their related intensities in the XRPD pattern are shown inTable 3. Form C is a polymorph of compound (I).

Characterization Methods:

XRPD: X-ray diffraction patterns were recorded at ambient conditions intransmission geometry with a STOE STADI P diffractometer with Cu-Kα1radiation. The diffractometer was equipped with a primary Ge beammonochromator and a silicon strip detector. Tube voltage was 40 KV andtube current was 40 mA. Scan range was from 3 to 42 degree 2-theta. Thestep size was 0.02 degree 2-theta with a measurement time of 20 s perstep. The samples were prepared and analyzed without further processing(e.g. grinding or sieving) of the substance.

DSC analysis: Mettler Toledo DSC1, 25-180° C., heating rate 10° C./min.

TGA analysis: Mettler Toledo TGA/DSC1, 25-350° C., heating rate 5°C./min.

TABLE 3 X-Ray powder diffraction peaks of Form C of compound (I). Pos.[°2-theta] Rel. Int. [%] 6.0 37 10.0 10 11.3 43 13.2 23 15.4 100 16.2 6417.9 13 18.1 31 19.3 20 20.0 34 20.5 13 21.4 34 21.6 13 23.5 33 24.3 924.6 61 25.6 16 26.1 34 27.3 13 31.0 11 32.5 17 34.0 12

DSC and TGA results shown in FIG. 4 and FIG. 5 indicate Form C ofcompound (I) has an onset melting temperature at around 128.9° C.

Example 5 Alternative Preparation of Form C of Compound (I).

Approximate 20 mg of Form Amorphous as prepared in Example 1 was weightinto a glass vial and approximate 0.05 mL of methanol was added. Theobtained solution was agitated at 25° C. overnight. The resultingsuspension was centrifuged, the supernatant was removed with a pipette,and the solid residue was further dried by inserting a small strip offilter paper for a few minutes. The solid was collected for XRPDanalysis. The XRPD pattern of the solid was the same as that in Table 3and confirmed to be Form C of compound (I).

Example 6 Alternative Preparation of Form C of Compound (I)

Approximate 100 mg of Form Amorphous as prepared in Example 1 wasweighed into a glass vial and approximate 0.05 mL of methanol was added.The resulting suspension was agitated at 25° C. for 2 h, then the solidwas collected by filtration and analyzed by XRPD. The XRPD pattern ofthe solid was same as that in Table 3 and confirmed to be Form C ofcompound (I).

Example 7 Alternative Preparation of Form C of Compound (I)

Approximate 40 mg of Form Amorphous of compound (I) as prepared inExample 1 was weighed and transferred to a glass vial, to whichapproximate 0.02 mL of ethanol was added to form a slurry. The vial wasmounted to a shaker and kept shaking at 25° C. at 1200 rpm for 2 h. Thesuspension was filtered and solid was collected for XRPD analysis. TheXRPD pattern of solid was same as that in Table 3 and confirmed to beForm C of compound (I).

Example 8 Alternative Preparation of Form C of Compound (I)

Approximate 40 mg of Form Amorphous of compound (I) as prepared inExample 1 was weighed and transferred to a glass vial, to whichapproximate 0.02 mL of acetone was added to form a slurry. The vial wasmounted to a shaker and kept shaking at 25° C. at 1200 rpm for 4 h. Thesuspension was filtered and solid was collected for XRPD analysis. TheXRPD pattern of solid was same as that in Table 3 and confirmed to beForm C of compound (I).

Example 9 Preparation of Form D of Compound (I)

Approximate 2.0 g of Form C of compound (I) as prepared in Example 4 wasweighed and transferred to a glass vial, to which 20 mL of ethyl acetatewas added to form a suspension. The suspension was filtered, thefiltrate was slowly evaporated and solid was collected for XRPDanalysis.

The XRPD pattern of Form D of compound (I) is shown in FIG. 6. Majorpeaks and their related intensities in the XRPD pattern are shown inTable 4. Form D is an ethyl acetate solvate of compound (I).

Characterization Method:

XRPD: PANalytical EMPYREAN X-ray powder diffractometer with Cu-Kαradiation. Tube voltage was 40 kV and tube current was 40 mA. Scan rangewas from 4 to 40 degree 2-theta. The step size was 0.026° at a scanningspeed of 3.463°/min.

TABLE 4 X-Ray Powder Diffraction peaks of Form D of compound (I). Pos.[°2-theta] Rel. Int. [%] 6.6 67 9.1 2 9.3 5 10.7 3 10.9 19 11.2 12 12.62 13.4 2 13.8 1 14.2 3 15.3 9 17.0 4 17.1 14 17.5 100 18.8 3 19.0 2119.4 2 20.0 1 20.5 63 20.8 43 21.6 5 21.9 5 22.1 7 22.5 1 22.9 5 23.2 123.4 2 24.0 5 24.2 18 24.7 1 25.4 22 26.1 30 26.7 1 26.9 2 27.2 1 27.6 228.0 1 28.7 58 29.1 2 29.3 1 29.7 2 30.6 2 31.7 3 33.3 28 33.7 2 34.3 234.9 2 35.2 5 35.3 3 35.9 1

FIG. 7 shows the X-ray structure of ethyl acetate solvate Form D. Thesingle crystal X-ray intensity data were collected at 130(2) K using aGemini R Ultra diffractometer (Rigaku) with Cu-K-alpha-radiation(1.54184 Å) and processed with the Crysalis package. Structure solutionand refinement was performed using the She1XTL software (Bruker AXS,Karlsruhe). The crystal data and structure refinement is shown in Table5.

TABLE 5 Single Crystal Structural Data of Forms D Crystal form Form DSolid form description Ethyl acetate monosolvate Measuring Temperature130 K Crystal system Orthorhombic Space group P2(1) 2(1) 2(1) Unit celldimensions a= 8.1962 Å b= 9.8708 Å c= 26.1518 Å α= 90° β= 90° γ= 90°Cell volume 2115.76 Å³ API molecules in unit cell 4 Calculated density1.389 g/cm³

Example 10 Preparation of Form A of Compound (I)

1000 mg of Form Amorphous of compound (I) was weighed and transferred toa glass vial then 0.3 mL of acetonitrile was added to form a slurry. Thevial was mounted to a shaker and kept shaking for 4 hours 25° C. at 1200rpm. The suspension was filtered and the solid was collected for XRPDanalysis. The XRPD pattern of Form A of compound (I) is shown in FIG. 8.Major peaks and their related intensities in the XRPD pattern are shownin Table 6. Depending on the solvation status Form A can be a solvate, ahydrate or a polymorph of compound (I).

Characterization Method:

DSC analysis: TA Q2000, 30-200° C., heating rate 10° C./min.

XRPD: X-ray diffraction patterns were recorded at ambient conditions intransmission geometry with a STOE STADI P diffractometer with Cu-Kα1radiation. The diffractometer was equipped with a primary Ge beammonochromator and a silicon strip detector. Tube voltage was 40 KV andtube current was 40 mA. Scan range was from 3 to 42 degree 2-theta. Thestep size was 0.02 degree 2-theta with a measurement time of 20 s perstep.

TABLE 6 X-Ray Powder Diffraction peaks of Form A of compound (I). Pos.[°2-theta] Rel. Int. [%] 3.7 100 6.5 99 7.5 24 9.9 4 11.2 2 12.1 11 12.622 13.5 2 14.2 7 15.2 23 16.4 22 16.5 23 16.9 11 17.2 14 18.2 2 19.3 520.0 5 20.8 14 21.4 12 21.8 4 22.1 12 22.4 17 22.7 23 23.4 16 24.6 1025.1 5 26.2 16 26.8 10 27.2 2 27.9 5 28.5 7 31.0 3 31.3 5 34.2 4 36.3 537.8 2 38.2 1 38.7 2

DSC result shown in FIG. 12 indicates Form A of compound (I) has anonset of endothermal event at around 75.9° C.

Example 11 Preparation of Form B of Compound (I)

Form A as prepared in Example 10 was suspended in water to form a slurryat room temperature for 2 hours to afford Form B, then the solid wascollected by filtration and dried under vacuum. Form B was characterizedby XRPD shown in FIG. 9. Major peaks and their related intensities inthe XRPD pattern are shown in Table 7. Depending on the solvation statusForm B can be a solvate, a hydrate or a polymorph of compound (I).

Characterization Method:

DSC analysis: TA Q2000, 30-200° C., heating rate 10° C./min.

XRPD: For crystalline form analysis, sample was mounted in a sampleholder on a goniometer and measured at ambient conditions. Data werecollected at 2-theta from 4 to 40° with a step size of 0.05° and ascanning speed of 1 s/step on a Bruker D8 Advance X-ray powderdiffractometer at 40 kV and 40mA. Cu-radiation of 1.54 Å wavelength wasused for data collection.

TABLE 7 X-Ray Powder Diffraction peaks of Form B of compound (I). Pos.[°2-theta] Rel. Int. [%] 4.9 100 6.5 30 8.3 36 10.0 21 10.3 21 13.3 4013.6 42 14.7 21 15.7 18 16.2 18 17.8 17 18.3 27 19.3 27 20.6 23 21.9 1922.3 21 23.1 30 24.5 32 25.3 30 25.9 37 27.2 19

DSC result shown in FIG. 13 indicates Form B of compound (I) has anonset of endothermal event at around 77.3° C.

Example 12 Preparation of Form G of Compound (I)

15 g of compound (I) was suspended at ambient temperature in 44.4 g ofacetone. The suspension was heated to 60° C. until complete dissolutionwas achieved. The dark yellow solution was cooled from 60° C. to 15° C.within approx. 1 hour. At 15° C. the solution was polish filtered andadded to 112.8 g of n-heptane (pre-cooled to 15° C.) while stirring. Theresulting suspension was stirred for 3 days at 15° C. before the solidwas isolated by filtration. Form G was characterized by XRPD shown inFIG. 10. Major peaks and their related intensities in the XRPD patternare shown in Table 8. Single crystal data can be found in Table 9. FormG is a polymorph of compound (I).

Characterization Method:

DSC analysis: Mettler Toledo DSC 2, 25-200° C., heating rate 10° C./min.

XRPD: X-ray diffraction patterns were recorded at ambient conditions intransmission geometry with a Stoe Stadi P diffractometer (Cu Kα1radiation (1.5406 Å), 40 kV and 40 mA, primary beam monochromator,silicon strip detector, angular range 3° to 42° 2-theta with a step sizeof 0.02° 2-theta, approximately 30 minutes total measurement time). Thesamples were prepared and analyzed without further processing (e.g.grinding or sieving) of the substance.

TABLE 8 X-Ray Powder Diffraction peaks of Form G of compound (I). Pos.[°2-theta] Rel. Int. [%] 5.9 49 9.6 40 9.9 12 12.6 97 15.9 80 17.9 3418.2 14 19.9 19 21.6 100 22.0 12 24.5 52 24.7 51 25.8 12 26.1 11 26.3 3829.1 17 32.7 15 33.1 24

DSC result shown in FIG. 14 indicates Form G of compound (I) has anonset melting temperature at around 122.0° C.

Single crystal diffraction: A single crystal was mounted in a loop andcooled to 100 K in a nitrogen stream. Data were collected at the Swisslight source beam line X10SA using a Pilatus detector with synchrotronradiation (0.70 Å) and data processed with the program XDS. The crystalstructure was solved and refined with the program She1XTL (Bruker AXS,Karlsruhe).

TABLE 9 Single Crystal Structural Data of Form G Crystal form Form GSolid form description free form Measuring Temperature 100 (2) K Crystalsystem Monoclinic Space group C2 Unit cell dimensions a= 30.543(6) Å b=5.5530(11) Å c= 9.4980(19) Å α= 90° β=     105.10(3)° γ= 90° Cell volume1555.3(6) Å³ API molecules in unit cell 4 Calculated density 1.513 g/cm³

Example 13 Preparation of Form F of Compound (I)

101.1 mg of Form C of compound (I) was suspended in 1 mL of water. Thesuspension was tumbled at 60° C. for 22 days, and the solid was isolatedas Form F by filtration. The product was dried for 4 days in a vacuumoven at 50° C./5 mbar.

The XRPD pattern of Form F of compound (I) is shown in FIG. 16. Majorpeaks and their related intensities in the XRPD pattern are shown inTable 10. Form F is a polymorph of compound (I).

Characterization Method:

DSC analysis: Mettler Toledo DSC 2, 25-200° C., heating rate 10° C./min.

XRPD: X-ray diffraction patterns were recorded at ambient conditions intransmission geometry with a Stoe Stadi P diffractometer (Cu Kα1radiation (1.5406 Å), 40 kV and 40 mA, primary beam monochromator,silicon strip detector, angular range 3° to 42° 2-theta with a step sizeof 0.02° 2-theta, approximately 30 minutes total measurement time). Thesamples were prepared and analyzed without further processing (e.g.grinding or sieving) of the substance.

TABLE 10 X-Ray Powder Diffraction peaks of Form F of compound (I). Pos.[°2-theta] Rel. Int. [%] 7.4 100 9.8 21 11.0 7 11.2 57 12.0 6 15.7 4516.0 98 16.4 78 17.2 74 18.1 24 18.4 9 18.8 22 19.2 27 21.0 54 21.2 2421.8 17 22.1 9 22.6 8 22.9 29 24.2 19 25.0 59 25.5 56 25.7 25 26.5 827.1 12 29.1 27 29.8 14 31.0 12 32.3 7 36.5 11

DSC result shown in FIG. 15 indicates Form F of compound (I) has anonset melting temperature at around 141.2° C.

Example 14 Preparation of Form H of Compound (I)

153.5 mg of Form C of compound (I) was dissolved in 2.85 mL of dimethylcarbonate at ambient temperature. The solution was filtered (0.45 μmPTFE filter). 6.3 mL of n-heptane was added and precipitation wasobserved. The suspension was stirred for one day at 22° C. The solid wasisolated as Form H by filtration and dried for 2 days in a vacuum ovenat 50° C./5 mbar.

The XRPD pattern of Form H of compound (I) is shown in FIG. 17. Majorpeaks and their related intensities in the XRPD pattern are shown inTable 11. Form H is a dimethyl carbonate solvate of compound (I).

Characterization Method:

XRPD: X-ray diffraction patterns were recorded at ambient conditions intransmission geometry with a Stoe Stadi P diffractometer (Cu Kα1radiation (1.5406 Å), 40 kV and 40 mA, primary beam monochromator,silicon strip detector, angular range 3° to 42° 2-theta with a step sizeof 0.02° 2-theta, approximately 30 minutes total measurement time). Thesamples were prepared and analyzed without further processing (e.g.grinding or sieving) of the substance.

TABLE 11 X-Ray Powder Diffraction peaks of Form H of compound (I). Pos.[°2-theta] Rel. Int. [%] 6.7 21 9.4 29 11.1 45 11.4 88 14.0 11 14.4 815.6 61 17.3 78 17.6 29 18.9 20 19.1 19 19.5 23 20.8 5 21.1 100 21.9 5622.0 16 22.2 10 23.2 43 23.7 19 24.7 13 25.8 46 28.5 15 28.8 19 29.0 4829.2 12 29.6 8 30.1 5 30.6 5 35.4 8 36.0 6 37.1 8 38.9 5

Single crystal diffraction: A single crystal was mounted in a loop andcooled to 100 K in a nitrogen stream. Data were collected at the Swisslight source beam line X10SA using a Pilatus detector with synchrotronradiation (0.70 Å) and data processed with the program XDS. The crystalstructure was solved and refined with the program She1XTL (Bruker AXS,Karlsruhe).

TABLE 12 Single Crystal Structural Data of Form H Crystal form Form HSolid form description free form Measuring Temperature 100(2) K Crystalsystem orthorhombic Space group P2(1)2(1)2(1) Unit cell dimensions a=8.0750(16) Å b= 10.056(2) Å c= 26.160(5) Å α= 90° β= 90° γ= 90° Cellvolume 2124.2(7) Å³ API molecules in unit cell 4 Calculated density1.390 g/cm³

Example 15 Preparation of Form I of Compound (I)

Approximately 306 mg of compound (I) (Form C) was suspended in 1.5 mL ofmethyl ethyl ketone. The suspension was tumbled at 22° C. for 55 days.The solid was isolated as Form I by filtration and dried overnight atambient temperature at 400 mbar.

The XRPD pattern of Form I of compound (I) is shown in FIG. 18. Majorpeaks and their related intensities in the XRPD pattern are shown inTable 13. Form I is a methyl ethyl ketone solvate of compound (I).

Characterization Method:

XRPD: X-ray diffraction patterns were recorded at ambient conditions intransmission geometry with a Stoe Stadi P diffractometer (Cu Kα1radiation (1.5406 Å), 40 kV and 40 mA, primary beam monochromator,silicon strip detector, angular range 3° to 42° 2-theta with a step sizeof 0.02° 2-theta, approximately 30 minutes total measurement time). Thesamples were prepared and analyzed without further processing (e.g.grinding or sieving) of the substance.

TABLE 13 X-Ray Powder Diffraction peaks of Form I of compound (I). Pos.[°2-theta] Rel. Int. [%] 9.4 23 11.1 94 13.5 6 13.8 16 14.2 22 15.4 4317.2 66 17.6 40 18.9 10 19.2 21 19.4 13 20.6 8 20.9 100 21.7 42 22.0 1822.4 8 23.0 33 23.3 8 24.0 22 25.2 25 25.3 14 25.6 4 26.9 5 27.9 11 28.79 28.9 23 29.3 5 29.6 4 29.9 4 30.9 5 31.0 4 33.6 7 34.1 7 35.0 12

Example 16 Preparation of Form J of Compound (I)

49.6 mg of Form B of compound (I) was dissolved in 2 mL of methylisobutyl ketone at 22° C. The vial was opened and stored for five daysto allow evaporation of the solvent at ambient condition, the resultingsolid was obtained as Form J.

The XRPD pattern of Form J of compound (I) is shown in FIG. 19. Majorpeaks and their related intensities in the XRPD pattern are shown inTable 14. Form J is a methyl isobutyl ketone solvate of compound (I).

Characterization Method:

XRPD: X-ray diffraction patterns were recorded at ambient conditions intransmission geometry with a Stoe Stadi P diffractometer (Cu Kα1radiation (1.5406 Å), 40 kV and 40 mA, primary beam monochromator,silicon strip detector, angular range 3° to 42° 2-theta with a step sizeof 0.02° 2-theta, approximately 30 minutes total measurement time). Thesamples were prepared and analyzed without further processing (e.g.grinding or sieving) of the substance.

TABLE 14 X-Ray Powder Diffraction peaks of Form J of compound (I). Pos.[°2-theta] Rel. Int. [%] 8.9 25 10.7 8 11.0 28 13.3 24 13.7 7 15.0 1116.4 29 16.9 15 17.8 7 19.8 100 20.7 31 22.1 7 22.6 20 22.8 5 23.7 2523.9 3 24.9 7 25.2 5 26.6 4 26.8 8 27.1 47 28.8 9 30.3 4 33.1 5 33.4 1035.1 4 36.0 4

Example 17 Stability of Solid Forms

40 mg compound (I) in different solid forms were stored in a stabilitychamber with temperature and humidity controlled at 40° C. and 75%-RH,respectively. After 1 month, the samples were analyzed by XRPD to checktheir solid form and compared with their initial solid form. Accordingto the results shown in Table 15. Form A, B, C, and G showed betterstability than the original amorphous form as prepared in Example 1.

TABLE 15 Physical stability data of different solid forms of compound(I) Physical stability Samples Initial 40° C./75%-RH, 1 month Example 1,Form Form solid form change Amorphous of compound (I) Amorphous Example10, Form A of Form A no solid form change compound (I) Example 11, FormB of Form B no solid form change compound (I) Example 2, Form C of FormC no solid form change compound (I) Example 12, Form G of Form G nosolid form change compound (I)

Example 18 Apparent Solubility Study

Apparent solubility was determined by suspending 5 mg of compound (I) indifferent bio-relevant media including pH buffers, SGF, FaSSIF, andFeSSIF. The suspensions were equilibrated at 25° C. for 24 hours. Thesuspensions were then filtered through a 0.22 μm PVDF filter into a 2-mLHPLC vial. The quantitaion of the filtrate was conducted by HPLC withreference to a standard solution. The solubility results of selectednovel solid forms in this invention are shown in Table 16. Surprisinglythe novel solid forms of this invention showed comparable apparentsolubility to Form Amorphous.

TABLE 16 Apparent solubility of different solid forms Sample Example 1,Form Example 12, Amorphous of Example 2, Form C Example 10, Form AExample 11, Form B Form G of compound (I) of compound (I) of compound(I) of compound (I) compound (I) Solubility Final Solubility FinalSolubility Final Solubility Final Solubility Final PH (mg/mL) pH (mg/mL)pH (mg/mL) pH (mg/mL) pH (mg/mL) pH pH 1 >10 1.1 >10 0.9 >16.28 1.2 >101.0 >10 1.0 pH 3 9.57 3.5 4.98 3.1 12.87 3.4 6.92 2.98 6.44 3.2 pH 53.83 5.2 2.24 4.9 6.39 5.0 3.35 4.73 3.75 5.1 pH 7 4.05 7.1 2.19 6.76.24 7.2 3.40 6.83 3.70 7.0 pH 9 5.03 9.1 2.32 8.8 6.38 8.9 3.55 8.863.64 8.9 SGF >10 1.3 >10 1.1 >16.36 1.5 >10 1.44 >10 1.2 FaSSIF 6.93 6.62.19 6.5 6.33 6.7 3.82 6.43 2.49 6.4 FeSSIF 7.35 5.2 2.78 4.9 7.93 5.04.13 4.93 2.79 5.1

Example 19 Single Dose PK (SDPK) Study

Five male Wistar Han rats were administered a single oral dose of 100 or200 mg/kg of compound (I) (either Form A or Form C). Drug wasadministered as a suspension in 2% klucel, 0.1% polysorbate 80 and 0.1%parabens in water. Samples were taken at various times up to 24 h andplasma was analysed for compound (I) (double prodrug), compound (Ia)(single prodrug) and compound (Ib) (single prodrug) and compound (III)(active Form).

compound (Ia) (single prodrug); compound (Ib) (single prodrug); compound(III) (active form)

TABLE 17 SDPK study of Form A and Form C of compound (I) in Wistar HanRat (n = 5) Compound Compound Compound Compound Parameter (I) (Ia) (Ib)(III) PO 100 mg/kg of Example 10, Form A of compound (I) T_(max) (h) 1.50.5 0.25 0.5 C_(max) (ng/mL) 563 24767 231 7103 PO 200 mg/kg of Example4, Form C of compound (I) T_(max) (h) 0.33 0.67 0.42 0.5 C_(max) (ng/mL)259 23233 258 5900

Compared with Form C of compound (I) dosing at 200 mg/kg, Form A ofcompound (I) dosing at 100 mg/kg exhibits faster conversion rate withshorter T_(max) and higher C_(max) for single prodrug (Ia) (0.5 h vs0.67 h; 24767 ng/mL vs 23233 ng/mL), and higher C_(max) of active form(7103 ng/mL vs 5900 ng/mL) in vivo study. Surprisingly Form A showscomparable or better SDPK profile than Form C even at half dose of thelater, therefore Form A of compound (I) whose efficacy is driven byC_(max) is more suitable to be formulated as immediate-release oralformulation.

1. A solid form of compound (I),

or salt, solvate, co-crystal or combination thereof.
 2. A solid formaccording to claim 1, wherein the form is Form Amorphous, Form A, FormB, Form C, Form D, Form E, Form F, Form G, Form H, Form I or Form J; ora combination thereof.
 3. A solid form according to claim 1 or 2,wherein the solid form is Form C that exhibits an X-ray powderdiffraction (XRPD) pattern with characteristic peaks expressed indegrees 2-theta at 6.0°±0.2°, 11.3°±0.2°, 15.4°±0.2°, 16.2°±0.2°,20.0°±0.2°, 21.4°±0.2°, 24.6°±0.2° and 26.1°±0.2°.
 4. A solid formaccording to claim 3, wherein the solid form is Form C that exhibits anX-ray powder diffraction (XRPD) pattern with characteristic peaksexpressed in degrees 2-theta at 6.0°±0.2°, 11.3°±0.2°, 13.2°±0.2°,15.4°±0.2°, 16.2°±0.2°, 18.1°±0.2°, 19.3°±0.2°, 20.0°±0.2°, 21.4°±0.2°,23.5°±0.2°, 24.6°±0.2°, 25.6°±0.2°, 26.1°±0.2° and 32.5°±0.2°.
 5. Asolid form according to claim 3 or 4, wherein the solid form is Form Cthat exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG.3.
 6. A solid form according to claim 1 or 2, wherein the solid form isForm D that exhibits an X-ray powder diffraction (XRPD) pattern withcharacteristic peaks expressed in degrees 2-theta at 6.6°±0.2°,17.5°±0.2°, 20.5°±0.2°, 20.8°±0.2°, 26.1°±0.2° and 28.7°±0.2°.
 7. Asolid form according to claim 6, wherein the solid form is Form D thatexhibits an X-ray powder diffraction (XRPD) pattern with characteristicpeaks expressed in degrees 2-theta at 6.6°±0.2°, 10.9°±0.2°, 11.2°±0.2°,15.3°±0.2°, 17.1°±0.2°, 17.5°±0.2°, 19.0°±0.2°, 20.5°±0.2°, 20.8°±0.2°,22.1°±0.2°, 24.2°±0.2°, 25.4°±0.2°, 26.1°±0.2°, 28.7°±0.2° and33.3°±0.2°.
 8. A solid form according to claim 6 or 7, wherein the solidform is Form D that exhibits an X-ray powder diffraction (XRPD) patternshown in FIG.
 6. 9. A solid form according to claim 1 or 2, wherein thesolid form is Form E that exhibits an X-ray powder diffraction (XRPD)pattern with characteristic peaks expressed in degrees 2-theta at6.4°±0.2°, 7.4°±0.2°, 7.6°±0.2°, 9.0°±0.2°, 13.4°±0.2°, 16.2°±0.2° and21.7°±0.2°.
 10. A solid form according to claim 9, wherein the solidform is Form E that exhibits an X-ray powder diffraction (XRPD) patternwith characteristic peaks expressed in degrees 2-theta at 6.4°±0.2°,7.4°±0.2°, 7.6°±0.2°, 9.0°±0.2°, 9.7°±0.2°, 13.4°±0.2°, 14.4°±0.2°,15.7°±0.2°, 16.2°±0.2°, 18.2°±0.2°, 21.0°±0.2°, 21.3°±0.2°, 21.7°±0.2°,23.5°±0.2° and 25.5°±0.2°.
 11. A solid form according to claim 9 or 10,wherein the solid form is Form E that exhibits an X-ray powderdiffraction (XRPD) pattern shown in FIG.
 2. 12. A solid form accordingto claim 1 or 2, wherein the solid form is Form A that exhibits an X-raypowder diffraction (XRPD) pattern with characteristic peaks expressed indegrees 2-theta at 3.7°±0.2°, 6.5°±0.2°, 7.5°±0.2°, 12.6°±0.2°,15.2°±0.2°, 16.4°±0.2°, 22.4°±0.2°, 22.7°±0.2° and 23.4°±0.2°.
 13. Asolid form according to claim 12, wherein the solid form is Form A thatexhibits an X-ray powder diffraction (XRPD) pattern with characteristicpeaks expressed in degrees 2-theta at 3.7°±0.2°, 6.5°±0.2°, 7.5°±0.2°,12.1°±0.2°, 12.6°±0.2°, 15.2°±0.2°, 16.4°±0.2°, 16.9°±0.2°, 20.8°±0.2°,21.4°±0.2°, 22.1°±0.2°, 22.4°±0.2°, 22.7°±0.2°, 23.4°±0.2°, 24.6°±0.2°,26.2°±0.2°, 26.2°±0.2° and 26.8°±0.2°.
 14. A solid form according toclaim 12 or 13, wherein the solid form is Form A that exhibits an X-raypowder diffraction (XRPD) pattern shown in FIG.
 8. 15. A solid formaccording to claim 1 or 2, wherein the solid form is Form B thatexhibits an X-ray powder diffraction (XRPD) pattern with characteristicpeaks expressed in degrees 2-theta at 4.9°±0.2°, 6.5°±0.2°, 8.3°±0.2°,13.3°±0.2°, 13.6°±0.2°, 24.5°±0.2° and 25.9°±0.2°.
 16. A solid formaccording to claim 15, wherein the solid form is Form B that exhibits anX-ray powder diffraction (XRPD) pattern with characteristic peaksexpressed in degrees 2-theta at 4.9°±0.2°, 6.5°±0.2°, 8.3°±0.2°,10.0°±0.2°, 10.3°±0.2°, 13.3°±0.2°, 13.6°±0.2°, 14.7°±0.2°, 18.3°±0.2°,19.3°±0.2°, 20.6°±0.2°, 22.3°±0.2°, 23.1°±0.2°, 24.5°±0.2°, 25.3°±0.2°and 25.9°±0.2°.
 17. A solid form according to claim 15 or 16, whereinthe solid form is Form B that exhibits an X-ray powder diffraction(XRPD) pattern shown in FIG.
 9. 18. A solid form according to claim 1 or2, wherein the solid form is Form G that exhibits an X-ray powderdiffraction (XRPD) pattern with characteristic peaks expressed indegrees 2-theta at 5.9°±0.2°, 12.6°±0.2°, 15.9°±0.2°, 21.6°±0.2°,24.5°±0.2° and 24.7°±0.2°.
 19. A solid form according to claim 15,wherein the solid form is Form G that exhibits an X-ray powderdiffraction (XRPD) pattern with characteristic peaks expressed indegrees 2-theta at 5.9°±0.2°, 9.6°±0.2°, 12.6°±0.2°, 15.9°±0.2°,17.9°±0.2°, 19.9°±0.2°, 21.6°±0.2°, 24.5°±0.2°, 24.7°±0.2°, 26.3°±0.2°,29.1°±0.2°, 32.7°±0.2° and 33.1°±0.2°.
 20. A solid form according toclaim 18 or 19, wherein the solid form is Form G that exhibits an X-raypowder diffraction (XRPD) pattern shown in FIG.
 10. 21. A solid formaccording to claim 1 or 2, wherein the solid form is Form F thatexhibits an X-ray powder diffraction (XRPD) pattern with characteristicpeaks expressed in degrees 2-theta at 7.4°±0.2°, 11.2°±0.2°, 16.0°±0.2°,16.4°±0.2°, 17.2°±0.2°, 21.0°±0.2°, 25.0°±0.2° and 25.5°±0.2°.
 22. Asolid form according to claim 21, wherein the solid form is Form F thatexhibits an X-ray powder diffraction (XRPD) pattern with characteristicpeaks expressed in degrees 2-theta at 7.4°±0.2°, 9.8°±0.2°, 11.2°±0.2°,15.7°±0.2°, 16.0°±0.2°, 16.4°±0.2°, 17.2°±0.2°, 18.1°±0.2°, 18.8°±0.2°,19.2°±0.2°, 21.0°±0.2°, 21.2°±0.2°, 22.9°±0.2°, 25.0°±0.2°, 25.5°±0.2°,25.7°±0.2° and 29.1°±0.2°.
 23. A solid form according to claim 21 or 22,wherein the solid form is Form F that exhibits an X-ray powderdiffraction (XRPD) pattern shown in FIG.
 16. 24. A solid form accordingto claim 1 or 2, wherein the solid form is Form H that exhibits an X-raypowder diffraction (XRPD) pattern with characteristic peaks expressed indegrees 2-theta at 11.4°±0.2°, 15.6°±0.2°, 17.3°±0.2°, 21.1°±0.2° and21.9°±0.2°.
 25. A solid form according to claim 24, wherein the solidform is Form H that exhibits an X-ray powder diffraction (XRPD) patternwith characteristic peaks expressed in degrees 2-theta at 6.7°±0.2°,9.4°±0.2°, 11.1°±0.2°, 11.4°±0.2°, 15.6°±0.2°, 17.3°±0.2°, 17.6°±0.2°,18.9°±0.2°, 19.5°±0.2°, 21.1°±0.2°, 21.9°±0.2°, 23.2°±0.2°, 25.8°±0.2°and 29.0°±0.2°.
 26. A solid form according to claim 24 or 25, whereinthe solid form is Form H that exhibits an X-ray powder diffraction(XRPD) pattern shown in FIG.
 17. 27. A solid form according to any oneof claims 24 to 26, wherein the Form H is a dimethyl carbonate solvateof compound (I).
 28. A solid form according to claim 1 or 2, wherein thesolid form is Form I that exhibits an X-ray powder diffraction (XRPD)pattern with characteristic peaks expressed in degrees 2-theta at11.1°±0.2°, 15.4°±0.2°, 17.2°±0.2°, 17.6°±0.2°, 20.9°±0.2° and21.7°±0.2°.
 29. A solid form according to claim 28, wherein the solidform is Form I that exhibits an X-ray powder diffraction (XRPD) patternwith characteristic peaks expressed in degrees 2-theta at 9.4°±0.2°,11.1°±0.2°, 13.8°±0.2°, 14.2°±0.2°, 15.4°±0.2°, 17.2°±0.2°, 17.6°±0.2°,19.2°±0.2°, 20.9°±0.2°, 21.7°±0.2°, 22.0°±0.2°, 23.0°±0.2°, 24.0°±0.2°,25.2°±0.2° and 28.9°±0.2°.
 30. A solid form according to claim 28 or 29,wherein the solid form is Form I that exhibits an X-ray powderdiffraction (XRPD) pattern shown in FIG.
 18. 31. A solid form accordingto any one of claims 28 to 30, wherein the Form I is a methyl ethylketone solvate of compound (I).
 32. A solid form according to claim 1 or2, wherein the solid form is Form J that exhibits an X-ray powderdiffraction (XRPD) pattern with characteristic peaks expressed indegrees 2-theta at 8.9°±0.2°, 11.0°±0.2°, 16.4°±0.2°, 19.8°±0.2°,20.7°±0.2°, 23.7°±0.2° and 27.1°±0.2°.
 33. A solid form according toclaim 32, wherein the solid form is Form J that exhibits an X-ray powderdiffraction (XRPD) pattern with characteristic peaks expressed indegrees 2-theta at 8.9°±0.2°, 11.0°±0.2°, 13.3°±0.2°, 15.0°±0.2°,16.4°±0.2°, 16.9°±0.2°, 19.8°±0.2°, 20.7°±0.2°, 22.6°±0.2°, 23.7°±0.2°,27.1°±0.2° and 33.4°±0.2°.
 34. A solid form according to claim 32 or 33,wherein the solid form is Form J that exhibits an X-ray powderdiffraction (XRPD) pattern shown in FIG.
 19. 35. A solid form accordingto any one of claims 32 to 34, wherein the Form J is a methyl isobutylketone solvate of compound (I).
 36. A pharmaceutical compositioncomprising the solid form of anyone of the claims 1 to 35 and apharmaceutically acceptable carrier, excipient, diluent, adjuvant,vehicle or a combination thereof.
 37. The use of the solid form of anyone of claims 1 to 35 or the pharmaceutical composition of claim 36 forthe manufacture of a medicament for the treatment or prophylaxis of aviral disease in a patient.
 38. The use according to claim 37, whereinthe viral disease is HBV infection.
 39. A method for the treatment orprophylaxis of HBV infection or a disease caused by HBV infection, whichmethod comprises administering a therapeutically effective amount of thesolid form as defined in any one of claims 1 to 35 or the pharmaceuticalcomposition of claim 36.